Quinoxaline moiety is a common component in a variety of biologically active drug-like molecules and has been found to be useful in the treatment of abnormal cell growth, such as cancer, in mammals. Hydroxyquinoxaline derivatives can be used as intermediates for the preparation of quinoxaline moiety and can be easily prepared from 1,2-phenylenediamine.
However, reactions of 3,4-disubstituted-1,2-phenylenediamine derivatives with glyoxylate or glyoxylic acid usually provide non-selective mixtures of 2-hydroxy-7,8-disubstitutedquinoxalines and regioisomeric 2-hydroxy-5,6-disubstitutedquinoxalines (Scheme A). These reactions are of limited utility not only due to their lack of regioselectivity and impact on overall yield, but also due to separation of the resulting isomers being generally extremely difficult and possibly requiring preparative chromatography, an often undesirable step in process sequence.

For example, PCT patent publications WO 2006/134378 A1, WO 2010/054229 A1, and WO 2014/139325 A1, and an article in the European Journal of Medicinal Chemistry (2018), 155, 135-152 describe quinoxaline derivatives and their uses as bioactivity agents. The preparation of such compounds involves synthesis of hydroxyquinoxaline as an intermediate by condensation of 1,2-phenylenediamine with glyoxylate or glyoxylic acid. The reaction usually provides a non-selective mixture of regioisomers of the desired product.
WO 2006/134378 A1, on page 138, describes a reaction that provides a mixture of isomers. Briefly, 3,4-Difluorobenzene-1,2-diamine (4.6 g, 31.6 mmol) and ethyl oxoacetate (50 wt % in toluene, 13.0 mL, 63.2 mmol) were reacted to give a mixture product of 3.7 g with 30% of the regioisomer 5,6-difluoroquinoxalin-2(1H)-one. (Scheme B).

WO 2010/054229 A1, on page 92, describes the preparation of hydroxyquinoxaline derivatives. Such a reaction provides a mixture of isomers. Briefly, 3-chlorobenzene-1,2-diamine (3.60 g, 25.3 mmol) and ethyl glyoxylate solution (50% in toluene; 6.0 mL, 30.3 mmol) were heated in ethanol (87 mL) to 75° C. for 18 hours. The reactants were then placed in a refrigerator to be cooled and the product was filtered to give 5-chloroquinoxalin-2(1H)-one as a rust colored solid (3.42 g). This crude product was purified by supercritical fluid chromatography to give 5-chloroquinoxalin-2(1H)-one and 8-chloroquinoxalin-2(1H)-one (Scheme C).

WO 2014/139325 A1, on pages 257 and 258, describes the preparation of hydroxyquinoxaline derivatives as intermediates. Such a reaction provides a mixture of isomers. Briefly, to a stirred suspension of ethyl 4-(2,3-diaminophenylsulfonamido) benzoate (5 g, 15 mmol) in ethanol (50 mL) was added a solution of ethyl glyoxylate in toluene (1.6 M, 3 mL, 18 mmol) over a period of 5 min. After heating to 45° C. for 10 h, the mixture was left at r.t. under stirring. The resulting product was a mixture of regioisomers (Scheme D).

European Journal of Medicinal Chemistry (2018), 155, 135-152, describes the preparation of hydroxyquinoxaline derivatives as intermediates, with such a reaction providing a mixture of isomers (Scheme E).

In addition, U.S. Pat. No. 5,169,955 discloses a process for producing a hydroquinoxaline which may be substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, and lower alkoxy. The process comprises reacting o-phenylenediamine which may be substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, and lower alkoxy with glyoxylic acid in a lower aliphatic alcohol solvent without using a catalyst.
These procedures, however, have the disadvantage of having low regioselectivity. The lack of regioselectivity requires the separation of the two regioisomers, considerably increasing production costs. It would be desirable to have a process for regioselective preparation of hydroxyquinoxaline.